3,4,5-trimethoxybenzamides of phenyl-and pyridylakylamines

ABSTRACT

3,4,5-Trimethoxybenzamides of pyridylalkylamines such as pyridylmethylamine and of phenylalkylamines such as phenylmethylamine, phenethylamine and Beta hydroxyphenethylamine, as well as derivatives thereof wherein the aromatic nucleus in the amine is substituted by one or more hydroxy, carboxy, halo, aryl, alkyl, nitro, alkoxy, aryloxy or thioalkoxy groups. The compounds are relatively non-toxic and are useful for pharmacological purposes. They exert a specific effect on the central nervous system and a somewhat lesser effect on muscle function. They are useful as relatively mild tranquilizers in the control of anxiety states, excessive aggressiveness and hyperactivity.

United States Patent Skinner et al.

3,676,447 July 11, 1972 [54] 3,4,5-TRIMETHOXYBENZAMIDES OF PHENYL-ANDPYRIDYLAKYLAMINES Inventors: Wilfred A. Skinner, Portola Valley; John G.Johansson, Palo Alto; Howard L. Johnson, Sunnyvale, all of Calif.

Stanford Research Institute, Melo Park, Calif.

Filed: June 24, 1970 Appl. No.: 49,518

Assignee:

[56] References Cited UNITED STATES PATENTS 2,870,156 l/l959 Perronetal...260/295 Primary Examiner-Alan L. Rothman Attorney-Donovan J. De Wittand Gregg, Hendricson & Caplan [5 7] ABSTRACT 3,4,5-Trimethoxybenzamidesof pyridylalkylamines such as pyridylmethylamine and ofphenylalkylamines such as phenylmethylamine, phenethylamine and,B-hydroxyphenethylamine, as well as derivatives thereof wherein thearomatic nucleus in the amine is substituted by one or more hydroxy,carboxy, halo, aryl, alkyl, nitro, alkoxy, aryloxy or thioalkoxy groups.The compounds are relatively non-toxic and are useful forpharmacological purposes. They exert a specific effect on the centralnervous system and a somewhat lesser effect on muscle function. They areuseful as relatively mild tranquilizers in the control of anxietystates, excessive aggressiveness and hyperactivity.

22 Claims, No Drawings 3 ,4,5TRIMETHOXYBENZAMIDES F PHENYL-ANDPYRIDYLAKYLAMINES SUMMARY OF THE INVENTTON The novel compounds of thepresent invention are those of the formula I Y H 1'1 1 c:i-n0-o-NR R orCHa) IIRB 1 1 C11 0 R R w 'otno- C-HR N CHQC II R6 R5 wherein Rrepresents a divalent methylene, ethylene or B- hydroxy ethylene group,and wherein the R R R, R and R groups, of which at least two arehydrogen, are selected from the group consisting of hydrogen, halo,alkyl, aryl, alkoxy, thioalkoxy, 'carboxy, aryloxy, hydroxy and nitro,as well as methylenedioxy, in which latter case the group collectivelyrepresents two adjacent R R R R or R groups. As employed herein, theterm alkyl and its derivative expressions designate a straight orbranched chain alkyl group containing from one to four carbon atoms,inclusive, such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl.The term aryl" and its derivative expressions designate aryl groups andalkyl substituted aryl groups, (both aralkyl and alkaryl) all containinga total of from six to eight carbon atoms, inclusive, such as benzyl,phenyl, tolyl or xylyl. The term halogen refers to the elementschlorine, bromine, fluorine and iodine.

The novel compounds of this invention are white solids, of distinctmelting point, which are soluble in some degree in benzene, petroleumether, ethyl ether, ethanol and other organic-solvents, and which aresubstantially insoluble in water. They are relatively non-toxic and haveutility in pharmacological applications. Thus, they can be employed inliving mammals as tranquilizers for the treatment and control ofanxiety, excessive aggressiveness and hyperactivity.

The compounds of the present invention can be prepared by reacting3,4,5-trimethoxybenzoyl chloride with the appropriatc amine reactant. Inone such method, set forth in detail below in Example I, the benzoylchloride is reacted with the amine in the presence of potassiumcarbonate in a solvent such as benzene, there being employedapproximately 1 mole of the benzoyl chloride for each amine moiety ofthe amine reactant which can if desired, by employed in excess. Thereaction mixture is first stirred at room temperatures for aboutone-half to four or more hours, following which the solution is heatedunder reflux conditions for an additional period of about one-half tothree or more hours. The solvent is then stripped off, leaving a residuewhich is washed first with water than with a 5 percent solution ofhydrochloric acid and finally with a 10 percent solution of sodiumcarbonate. The residue is taken up in benzene and is re-crystallizedtherefrom. In another method, which is set forth in detail below inExample 2, the amine is reacted with the benzoyl chloride usingapproximately a 100 percent mole excess of the amine, said excessserving to take up the hydrogen chloride biproduct formed during thereaction. ln this operation, the reactants, in a solvent such asbenzene, are stirred at room temperatures for several hours, followingwhich the solution is washed first with 5 percent hydrochloric acid,then with 10 percent sodium carbonate and finally with water. Thesolvent is then stripped off, following which the product is taken up inand recrystallized from a suitable solvent such as benzene or benzeneadmixed with ethanol, cyclohexane or the like.

The 3,4,5-trimethyoxybenzoyl chloride employed as a starting material isavailable commercially from Aldrich Chemical Company, Inc., Milwaukee,Wisconsin, and others. It can be prepared in a conventional fashion byreacting 3,4,5- trimethoxybenzoic acid with an excess of thionylchloride in a solvent such as chloroform or benzene, the reactionproceeding readily at reflux temperatures. The product can be recoveredby stripping off the solvent along with decomposition products of theexcess thionyl chloride.

The amine compounds which are employed as starting materials can beprepared by methods which are well known to those skilled in the art.For example, those of the amines wherein R is a ,B-hydroxyethylene groupcan be prepared by one or another of the two following methods. Thefirst such method involves reacting the corresponding acetophenonecompound (containing the desired R R", R", R and R substituent groups)with an approximately equimolar amount of trimethylphenylammoniumtribromide in a solvent such as tetrahydrofuran to form thecorresponding a-bromoacetophenone intermediate. This reaction takesplace at room temperatures as the reaction mixture is stirred for anumber of hours, following which the brominated phenone compound isrecovered by stripping off the solvent and recrystallizing the compoundfrom a suitable solvent such as mixed ethanolpetroleum ether. The bromointermediate is then reacted with an excess of sodium azide in methanolfor several hours at room temperatures, following which the solvent isstripped off, water is added and the product is extracted with ethylether. The ether phase is dried (anhydrous Na SO,,) and the solvent isevaporated off, leaving the corresponding azide intermediate. This isthen reduced with either lithium hydride or sodium borohydride followedby catalytic reduction with platinum oxide. When using platinum oxide,reduction is affected at room temperatures and atmospheric pressures inethanol, following which the solvent is stripped off and the product istaken up in IN l-lCl. After being washed with ethyl ether, the acidsolution is made alkaline with sodium carbonate and extracted with ethylether. The ether phase is then dried (Na SO and the ether evaporated toleave the desired amine product. The reduction step with lithiumaluminum hydride is described in the method to follow.

In the other method a benzaldehyde starting compound is converted to thecorresponding cyanohydrin by reaction with sodium acid sulfite andsodium cyanide, using the method of Levine et al, Jnl. Chem. Soc. 70,1930 (1948). The cyanohydrin is then converted to the desiredhydroxyphenethylamine by reduction with lithium aluminum hydride usingthe method of 0.1. Poos et al, Jnl. Med. Chem. 6, 266 (i963 In preparingamines wherein R is methylene or ethylene, the correspondingphenylacetonitriie or phenylpropionitrile compound is catalyticallyreduced to the desired amine product using Raney nickel inammonia-saturated ethanol.

Representative amine compounds which can be employed to react with the3,4,5-trimethoxybenzoyl chloride include the following:

B-hydroxy-B-phenethylamine phenylmethylamine B-phenethylamine4-(aminomethyl)-pyridine 4-(aminoethyl)-pyridine4-(aminomethyl)-2-methoxypyridine (3,S-dimethoxyphenyl)-ethylamineB-(p-ethoxyphenyl)-,B-hydroxyethylamineB-(3,4,5-trimethoxyphenyl)-/3-hydroxyethylaminefi-(4-biphenylyl)-B-hydroxyethylamine [3-(p-methoxyphenyl)-B-hydroxyethylaminefi-(o-chlorophenyl)-B-hydroxyethylamineB-(m-bromophenyl)-B-hydroxyethylamine B-(3,4-methylenedioxyphenyl)-B-hydroxyethylamineB-(3-fluoro-4-methoxyphenyl)-B-hydroxyethylamine B( 2,6-dichlorophenyl)-fl-hydroxyethylamine B-( 2,5-dimethoxyphenyl )-B-hydroxyethylamineB-(pisopropylphenyl)-fi-hydroxyethylamineB-(3-methoxy-4-ethoxyphenyl)-B-hydroxyethylamineB-(m-methoxyphenyl)-B-hydroxyethylamine,B-(o-methoxyphenyl)-B-hydroxyethylamine B-( 2,4-dimethoxyphenyl)-B-hydroxyethylamine ;3( 3,4-dibenzyloxyphenyl)-B-hydroxyethylamineB-(o-methylphenyl)-fl-hydroxyethylamine/3-(o-bromophenyl)-fl-hydroxyethy1amine (3-carboxy-4-hydroxyphenyl)-methylamine fl-( 2-hydroxy-3-methoxyphenyl )-B-hydroxyethylamineB-(2,6-dimethoxyphenyl)-}S-hydroxyethy1amine B-( 3 ,4,5-trimethoxyphenyl )-ethylamine 4-( amino-B-hydroxyethyl )-pyridine4-(amino-B-hydroxyethyl)-picolinic acid 4-aminoB-hydroxyethyl)-2-ch1oropyridine 4-(aminornethyl )-2-nitropyridine4-(aminomethyl)-2-thiomethoxy pyridine /3-( p-thiomethoxyphenyl)-B-hydroxyethylamine B-(m-nitrophenyl )-fi-hydroxyethylaminefl-(m-xylylphenyl )-B-hydroxyethy1amine /3-( p-tolylphenyl)-,B-hydroxyethy1aminc [3-(oiodopheny1)-B-hydroxyethylamine DESCRlPTlONOF PREFERRED EMBODIMENTS The following examples are merely illustrativeof the invention and are not to be construed as limiting.

Example 1 3,4,5-trimethoxybenzamide ofB-(p-ethoxphenyl)-B-hydroxyethylamine 3,4,5-trimethoxybenzoyl chloridein the amount of 2.3 g (0.01 mole) is dissolved in 125 ml of benzenealong with 3 g (0.016 mole) of B-(p-ethoxyphenyl)-/3-hydroxyethylamineand 3 g of potassium carbonate to take up the HO] found during thereaction. The reaction mixture is stirred for 5 hours at roomtemperature, following which the benzene is distilled off and theproduct is washed first with water, then with a 5 percent hydrochloricacid solution and finally with a percent sodium carbonate solution. Theproduct is then taken in benzene and recrystallized therefrom, therebeing recovered 1.4 g of a white solid having a melting point of l36138C. which is soluble in benzene, ethanol and other organic solvents andsubstantially insoluble in water. The identity of the product isconfirmed by elemental analysis which discloses the compound to be onehaving carbon, hydrogen and nitrogen contents of 63.62, 6.80 and 3.65percent, respectively, versus calculated values of 63.99, 6.71 and 3.73percent, respectively, for these elements in the amide compound formingthe caption of this example.

Example 2 3,4,5-trimethoxybenzamide of fi-hydroxy-[S-phenethylamine3,4,S-trimethoxybenzoy1 In this operation, 3.46 g (0.015) of3,4,5-trimethoxybenzoyl chloride is dissolved in 125 ml of benzene alongwith 4.12 g (0.03 mole) of fi-hydroxy B-phenylethylamine. The resultingsolution is stirred at room temperatures for 5 hours, with small amountsof benzene being added from time to time to keep the formed amide in thesolution. The solution is then washed first with 5 percent hydrochloricacid, then with 10 percent sodium carbonate and finally with water. Thesolvent is then evaporated and the residue is taken up in benzene andrecrystallized therefrom, there thus being recovered a 3.4 g of a whitesolid having a melting poing of 98.599.5 C. which is soluble in benzene,ethyl ether and other organic solvents and substantially insoluble inwater. The identity of the compound is confirmed by elemental analysiswhich discloses it to be one having carbon, hydrogen and nitrogencontents of 65.06, 6.37 and 4.14 percent, respectively versus calculatedvalues of 65.24, 6.39 and 4.23 percent, respectively, for these elementsin the amide compound which forms the caption of this examp In thefollowing examples, the 3,4,5-trimethoxybenzoy1 chloride is reacted withthe indicated amine to form the captioned amide. In each case the methodused is substantially that of Example 2 except where the method isindicated to be that of Example 1. All the compounds are soluble inorganic solvcnts and not soluble in water.

EXAMPLE 3 EXAMPLE 4 3,4,5-trimethoxybenzamide ofB-(4-biphenylyl)-B-hydroxyethylamine Following substantially theprocedure of Example 1, the foregoing compound is obtained as a whitesolid having a melting point of 169-l70 C. C,H,N; found: 70.56, 6.27,3.53; calculated: 70.74, 6.18 and 3.44 percent.

EXAMPLE 5 3,4,5-trimethoxybenzamide ofB-(p-methoxyphenyU-fihydroxyethylamine The foregoing compound isobtained as a white solid having a melting point of ll3-ll4 C. C,H,N;found: 63.00, 6.44,

3.67; calculated: 63.15, 6.41 and 3.88 percent.

EXAMPLE 6 3,4,5-trimethoxybenzamide ofB-(o-chlorophenyl)-B-hydroxyethylamine The foregoing compound isobtained as a white solid having a melting point of 98.5-l0 C. C,H,N;found: 59.01, 5.70, 3.68; calculated: 59.3, 5.50 and 3.82 percent.

EXAMPLE 7 3,4,5-trimethoxybenzamide of B-(m-bromo-phenyU-B-hydroxyethylamine Following substantially the procedure of Example 1,the foregoing compound is obtained as a white solid having a meltingpoint of l22.5l24.5 C. C,H,N; found: 53.13, 5.10,

3.34; calculated: 52.8, 4.92 and 3.46 percent.

EXAMPLE 8 3,4,5-trimethoxybenzamide ofB-(3,4-methyl-enedioxyphenyl)-B-hydroxyethy1amine The foregoing compoundis obtained as a white solid having a melting point of l02104 C. C,H,N;found: 60.57, 5.70, 3.57; calculated: 60.79, 5.64 and 3.73 percent.

EXAMPLE 9 3,4,5-trimethoxybenzamide ofB-(3-fluoro-4-methoxyphenyl)-B-hydroxyethylamine Following substantiallythe procedure of Example 1, the foregoing compound is obtained as awhite solid having a melting point of l20.5121.5C. C,H,N; found: 60.00,5.99, 3.70; calculated: 60.21, 5.85 and 3.70 percent.

EXAMPLE l0 3,4,5-trimethoxybenzamide of B-(2,6-dich1oropheny1)-/3-hydroxyethylamine The foregoing compound is obtained as a white solidhaving a melting point of l00-l02 C., and containing 1 mole of water ofhydration. Including this water, the values obtained by elementalanalysis are as follows: C,l-1,N; found: 51.48, 5.15, 3.23; calculated:51.7, 5.05 and 3.35 percent.

EXAMPLE ll 3,4,5-trimethoxybenzamide of B-(2,5-dimethoxyphenyl)-B-hydroxethylamine The foregoing compound is obtained as a white solidhaving a melting point of 166.5-167 C. C,H,N; found: 61.52, 6.32, 3.56;calculated: 61.37, 6.44 and 3.58.

EXAMPLE l2 3,4,5-trimethoxybenzamide of p-(p-isopropylphenyl)-/3-hydroxyethylamine Using substantially the procedure of Example 1, theforegoing compound is obtained as a white solid having a melting pointof l28l28.5 C. C,H,N; found: 67.30, 7.38, 3.61; calculated: 67.54, 7.29and 3.75 percent.

EXAMPLE 13 EXAMPLE l4 3,4,5-trimethoxybenzamide of hydroxyethylamine Theforegoing compound is obtained as a white solid having a melting pointof 98.599.5 C C,H,N; found: 62.85, 6.64,

3.81; calculated: 63.15, 6.41 and 3.88 percent.

fl-(m-methoxyphenyD-B- EXAMPLE l5 3,4,5-trimethoxybenzamide ofhydroxyethylamine The foregoing compound is obtained as a white solidhaving a melting point of 155l55.5 C. C,H,N; found: 62.76, 6.36,

3.84; calculated: 63.15, 6.41 and 3.88 percent.

B-(o-methoxyphenyU-B- EXAMPLE 16 3,4,5-trimethoxybenzamide offi-(2,4-dimethoxyphenyl)-B- hydroxyethylamine The foregoing compound isobtained as a white solid having a melting point of 148149 C. C,H,N;found: 61.49, 6.56, 3.68; calculated: 61.37, 6.44 and 3.58 percent.

EXAMPLE 17 3,4,5-trimethoxybenzamide offi-(o-fluorophenyl)-B-hydroxyethylamine The foregoing compound isobtained as a white solid having a melting point of 111-112 C. C,H,N;found: 62.02, 5.99, 4.09; calculated: 62.0, 5.78 and 4.01 percent.

EXAMPLE 18 2,3,5-trimethoxybenzamide ofB-(2-hydroxy-3-methoxyphenyl)-fihydroxyethylamine Using substantiallythe procedures of Example 1, the foregoing compound is obtained as awhite solid having a melting point of 180-181.5 C. C,H,N; found: 60.46,6.21, 3.70; calculated: 60.47, 6.14 and 3.71 percent.

EXAMPLE 19 3,4,5-trimethoxybenzamide of B-(3,4-dibenzyloxyphenyl)-B-hydroxyethylamine The foregoing compound is obtained as a white solidhaving a melting point of 147-147.5 C. C,H,N; found: 70.75, 6.26, 2.69;calculated: 70.70, 6.12 and 2.58 percent.

EXAMPLE 20 3,4,5-trimethoxybenzamide ofB-(o-methylphenyl)-B-hydroxyethylamine The foregoing compound isobtained as a white solid having a melting point of 84.586.5 C. C,H,N;found: 65.78, 6.72, 4.12; calculated: 66.07, 6.71 and 4.06 percent.

EXAMPLE 21 3,4,5-trimethoxybenzamide ofB-(o-bromo-phenyl)-B-hydroxyethylamine The foregoing compound isobtained as a white solid having a melting point of 121122 C. C,H,N;found: 52.49, 5.02, 3.56; calculated: 52.8, 4.92, and 3.46 percent.

EXAMPLE 22 3,4,5-trimethoxybenzamide of (3-carboxy-4-hydroxyphenyl)-methylamine Following the procedure of Example 1, the foregoing compoundis prepared as a white solid having a melting point of 206.5-207.5 C.C,H,N; found: 59.83, 5.38 and 4.01; calculated: 59.83, 5.30 and 3.88percent.

EXAMPLE 23 3,4,5trimethoxybenzamide of B-(3,4,5-trimethoxyphenyl)-ethylamine The foregoing compound is obtained as a white solid having amelting point of 183184 C. C,H,N; found: 62.51, 6.84, 3.61; calculated:62.21 6.71 and 3.45 percent EXAMPLE 24 3,4,5-trimethoxybenzamide ofB-(2,6-dimethoxyphenyl)- ethylamine The foregoing compound is preparedas a white powder having a melting point of 193194 C. C,H,N; found:63.86,

6.51 and 3.74; calculated: 63.99, 6.71 and 3.73 percent EXAMPLE 253,4,5-trimethoxybenzamide of 4-(aminomethyl)-pyridine The foregoingcompound is obtained as a white powder having a melting point of 159162C. C,H,N; found: 63.21, 5.87, 9.32; calculated: 63.56, 6.0 and 9.27percent.

EXAMPLE 26 3,4,5-trimethoxybenzamide of fi-(2,4,6-triiodophenyl)-ethylamine The foregoing compound is obtained as a white powder having amelting point of 188-189.5 C. This structure is confirmed by elementalanalysis.

EXAMPLE 27 3,4,5-trimethoxybenzamide of 4-(amino-B-hydroxyethyl)-pyridine The foregoing compound is obtained having a molecular weight of332.36.

EXAMPLE 28 3,4,5-trimethoxybenzamide of 4-(amino-B-hydroxyethyl)-picolinic acid The foregoing compound is obtained having a molecularweight of 376.37.

EXAMPLE 29 3,4,5-trimethoxybenzamide of 4-(amino-B-hydroxyethyl)-2-chloropyridine The foregoing compound'is obtained having a molecularweight of 366.81.

EXAMPLE 30 3,4,5-trimethoxybenzamide of 4'( aminoethyl)-2-nitropyridineThe foregoing compound is obtained having a molecular weight of 361 .37.

EXAMPLE 31 3,4,5-trimethoxybenzamide thiomethoxypyridine The foregoingcompound is obtained having a molecular weight of 348.42.

of 4-(aminomethyl )-2- EXAMPLE 32 3,4,5-trimethoxybenzamide ofB-(p-thiomethoxyphenyl)-B- hydroxyethylamine The foregoing compound isobtained having a molecular weight of 377.47.

EXAMPLE 33 3,4,5-trimethoxybenzamide offi-(m-nitro-phenyl)-fi-hydroxyethylamine The foregoing compound isobtained having a molecular weight of 376.39.

EXAMPLE 34 3,4,5'trimcthoxybcnzamidc of[3-(m-xylylphenyU-B-hydroxycthylaminc The foregoing compound is obtainedhaving a molecular wcightof435.49.

EXAMPLE 35 3,4,5-trimcthoxybenzamide ofB-(p-tolyl-phenyl)-B-hydroxycthylamine The foregoing compound isobtained having a molecular weight of42 1 .45.

EXAMPLE 36 3,4,5-trimethoxybenzamide of phenylmethylamine The foregoingcompound is obtained having a molecular weight of 301.35.

EXAMPLE 37 3,4,5-trimethoxybenzamide of B-phenethylamine The foregoingcompound is obtained having a molecular weight of3 l 5.38.

EXAMPLE 38 3,4,5-trimethoxybenzamide of 4-(aminoethyl)-pyridine Theforegoing compound is obtained having a molecular weight of 3 16.36.

EXAMPLE 39 3,4,5-trimethoxybenzamide of4-(aminomethyl)-2-methoxypyridine The foregoing compound is obtainedhaving a molecular weight of 332.36.

The compounds of this invention are useful as sedatives and arecharacterized, in general, by the fact that their effects on coordinatedmotor activity are independent of their effects on uncoordinated motoractivity. Thus, when administered either orally or by injection into amammal, said compounds are capable of providing a sedative effectwithout at the same time inducing a corresponding of properties makesthe compounds well adapted to be employed in the treatment of anxietystates, excessive aggressiveness and hyperactivity.

In evaluating the degree and type of central nervous system depressionexerted thereby, the compounds hereof were administered to mice and theresultant effects were determined by the photocell-activity-cage(uncoordinated motor activity) and the rotorod (coordinated motoractivity) methods. These methods are essentially those which aredescribed by Kinnard and Carr, .lnl. Phannacol. Exptl. Therapy., 121,354 (1957). In carrying out these determinations, male albino mice(17-20 g) of a Swiss-Webster strain were utilized, and were used onlyonce. All drugs were administered intraperitoneally as suspensions inpercent Tween 80 in 0.9 percent saline (0.2 ml). Photocell activity wasdetermined as cumulative counts over a 1 hour period beginning 0.5 hourafter administration of drug or vehicle to groups of five mice. Activitywas determined for one control group with each two treatment groups.Values for the latter were calculated as percentages of the former andare so expressed in the following table. Rotarod performance times weredetermined in groups of five trained mice 0.5 hour after administrationof drug or vehicle. Mean performance time for control groups was 113.9sec. and rod rotation as at the rate of rpm. The mean performance timesfor the treated mice are expressed as a percentage of the control groupperformance time in the table.

The results obtained in the foregoing tests are expressed in thefollowing table, wherein each test compound employed is designated bythe particular Example hereof in which the compound is described.

Compound Dose Photocell Rotorod Employed mg/kg of Activity Cage of(Example Body of Control) Number) Weight) 1 Std. Error Control 3 I00 3lI 4 87 4 100 4l i 8 82 5 50 49 1 4 96 6 50 60 i 5 97 I2 50 37 i 3 89 I325 43 i 2 75 I4 150 25 i: 8 90 IS 25 35 1 9 85 i6 W0 32 i 2 94 17 S0 57:2: l4 99 l8 25 36 i 6 19 100 62 t I0 90 23 I00 47 i 3 82 24 100 45 i- 990 25 50 42 t. 13 93 10 50 37 i 4 85 We claim: 1. Compounds having theformula CH O R R (I? 1;]: I l CHQO CNR -R or I l l CH3O R R CHQO R R 0 NI l l I CH O- O-HR N l CH O II R R wherein R represents --Cl*l CH(OH)and wherein R R", R, R" and R, of which at least two are hydrogen, areselected from the groups consisting of hydrogen, halo, alkyl, aryl,alkoxy, thioalkoxy, carboxy, aryloxy, hydroxy, nitro and OCl-l O--groups, the term alkyl" representing an alkyl group of from one to fourcarbon atoms and the term "aryl" representing aryl, alkaryl and aralkylgroups, all of from six to eight carbon atoms.

2. The compound of claim 1 which is the 3,4,5-trimethoxybenzamide ofB-(p-ethoxphenyl)-B-hydroxyethylamine.

3. The compound of claim 1 which is the 3,4,5-trimethoxybenzamide ofB-hydroxy-B-phenethylamine.

4. The compound of claim 1 which is the 3,4,5-trimethoxybenzamide offi-(3,4,5-trimethoxyphenyl)-B-hydroxyethylamine.

5. The compound of claim 1 which is the 3,4,5-trimethoxybenzamide ofB-(S,4,5biphenylyl)-fi-hydroxyethylamine.

6. The compound of claim 1 is the 3,4,5-trimethoxybenzamide offi-(p-methoxyphenyl)-B-hydroxyethylamine.

7. The compound of claim 1 which is the 3,4,5-trimethoxybenzamide ofB-(o-chlorophenyl)-fl-hydroxyethylamine.

8. The compound of claim 1 which is the 3,4,5-trimethoxybenzamide offl-(m-bromophenyl)-B-hydroxyethylamine.

9. The compound of claim 1 which is the 3,4,5-trimethoxybenzamide ofB-(3,4-methylenedioxyphenyl)-fl-hydroxyethylamine.

10. The compound of claim 1 which is the 3,4,5-trimethoxybenzamide ofB-(3-fluoro-4-methoxyphenyl)-B-hydroxyethylamine.

' 11. The compound of claim 1 which is the 3,4,5-trimethoxybenzamide ofB-(2,6-dichlorophenyl)-B-hydroxyethylamine.

12. The compound of claim 1 which is the 3,4,5-trimethoxybenzamide ofB-(2,5-dimethoxyphenyl)-B-hydroxyethylamine.

' ybenzamide of B-(2,4-dimethoxyphenyl)-B-hydrox- 13. The compound ofclaim 1 which is the 3,4,5-trimethoxybenzamide ofB-(0-fluorophenyl)-fi-hydroxyethylamine. ybenzamide 0f B-(pp py p y)-fi-hydroxyeth lamine. 19. The compound of claim 1 which is the3,4,5-trimethox- 14. compound of claim 1 iS the3,4,5-trimeth0xybenzamide of B (2-hydroxy-3-methoxyphenyl)fi-hydroxybenzamide of B-(3-methoxy-4-ethoxyphenyl)-B-hydroxh 1 i y y20. The compound of claim 1 which is the 3,4,5-trimethox- 15. Thecompound of claim 1 which 15 the 3,4,5-trime thoxybenzamide of fi (34dibenzyloxyphenyl) fl hydmx ybenzamlde ofB-(m-methoxyphenyl)-fi-hydroxyethylamme. yethylamine 16. The compound ofclaim 1 which is the 3,4,5-trimethox- The compound of claim 1 which isthe 345 trimethox ybenzamide ofB-(o-methoxyphenyl)-fi-hydroxyethylamine.

ybenzamlde of B-(o-methylphenyl)-B-hydroxyethylam1ne. 17. The compoundof claim 1 WhlCh 15 the 3,4,5 trlmethox 22- The compound of claim 1which is the 3,4,54rimethox yethylamine ybenzamide ofB-(o-bromophenyl)-B-hydroxyethylamine.

18. The compound of claim 1 which is the 3,4,5-trimethox-

2. The compound of claim 1 which is the 3,4,5-trimethoxybenzamide ofBeta -(p-ethoxphenyl)- Beta -hydroxyethylamine.
 3. The compound of claim1 which is the 3,4,5-trimethoxybenzamide of Beta -hydroxy- Beta-phenethylamine.
 4. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(3,4,5-trimethoxyphenyl)- Beta-hydroxyethylamine.
 5. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(3,4,5biphenylyl)- Beta-hydroxyethylamine.
 6. The compound of claim 1 is the3,4,5-trimethoxybenzamide of Beta -(p-methoxyphenyl)- Beta-hydroxyethylamine.
 7. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(o-chlorophenyl)- Beta-hydroxyethylamine.
 8. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(m-bromophenyl)- Beta-hydroxyethylamine.
 9. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(3,4-methylenedioxyphenyl)- Beta-hydroxyethylamine.
 10. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(3-fluoro-4-methoxyphenyl)- Beta-hydroxyethylamine.
 11. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(2,6-dichlorophenyl)- Beta-hydroxyethylamine.
 12. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(2,5-dimethoxyphenyl)- Beta-hydroxyethylamine.
 13. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(p-isopropylphenyl)- Beta-hydroxyethylamine.
 14. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(3-methoxy-4-ethoxyphenyl)- Beta-hydroxyethylamine.
 15. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(m-methoxyphenyl)- Beta-hydroxyethylamine.
 16. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(o-methoxyphenyl)- Beta-hydroxyethylamine.
 17. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(2,4-dimethoxyphenyl)- Beta-hydroxyethylamine.
 18. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(0-fluorophenyl- Beta-hydroxyethylamine.
 19. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(2-hydroxy-3-methoxyphenyl)- Beta-hydroxyethylamine.
 20. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(3,4-dibenzyloxyphenyl)- Beta-hydroxyethylamine.
 21. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(o-methylphenyl)- Beta-hydroxyethylamine.
 22. The compound of claim 1 which is the3,4,5-trimethoxybenzamide of Beta -(o-bromophenyl)- Beta-hydroxyethylamine.